M. Balíková: The Fate of Poison1 TOXICOLOGY I. The fate of poison in organism M. Balíková

M. Balíková: The Fate of Poison 1

TOXICOLOGYTOXICOLOGY

I. The fate of poison in organismI. The fate of poison in organism

M. BalíkováM. Balíková


What is the poisonWhat is the poisonThe substance which after the resorption into The substance which after the resorption into the blood stream can induce the harmful effects the blood stream can induce the harmful effects to the organism to the organism Toxic effectsToxic effects::

contemporarycontemporary with permanent damage to organswith permanent damage to organs fatal fatal

Mutual action between poison and organism:Mutual action between poison and organism:

PHARMACODYNAMICS PHARMACODYNAMICS (What does the poison (What does the poison to the organism?)to the organism?)

PHARMACOKINETICSPHARMACOKINETICS (What does the organism (What does the organism to the poison?)to the poison?)


The fate of poison in The fate of poison in organismorganism

ApplicationApplication mode and mode and bioavailability,metabolismbioavailability,metabolism

Inhalation-Sniffing-Injection-Ingestion-Dermal ResorptionResorption into blood stream into blood stream Distribution into tissuesDistribution into tissues BiotransformationBiotransformation into metabolites into metabolites Elimination waysElimination ways::

a) Urine – polar compoundsa) Urine – polar compoundsb) Feaces – lipophilic compoundsb) Feaces – lipophilic compoundsc) Lungs – gases, volatiles c) Lungs – gases, volatiles d) Hair – deposits of basic compounds above alld) Hair – deposits of basic compounds above alle) Saliva – hydrophilic/lipophilice) Saliva – hydrophilic/lipophilicf) Sweat – hydrophilic/lipophilicf) Sweat – hydrophilic/lipophilic


OVERVIEWOVERVIEW


The individual variation in The individual variation in pharmacokinetics and pharmacokinetics and

pharmacodynamicspharmacodynamics

Genetics (e. g. variation among races)Genetics (e. g. variation among races) SexSex AgeAge Actual health stateActual health state Life style, toleranceLife style, tolerance The mode of application, drug mixturesThe mode of application, drug mixtures

a) Variation in effects (receptors)a) Variation in effects (receptors)

b) Variation in metabolism b) Variation in metabolism (enzymes)(enzymes)


Biotransformation:Biotransformation:

Modification of the chemical Modification of the chemical structure of parent compound in structure of parent compound in organism, catalysed by enzymesorganism, catalysed by enzymes

Metabolites with different potencyMetabolites with different potency

Most of enzymes bound in hepatocytesMost of enzymes bound in hepatocytes

The liver and the first pass metabolismThe liver and the first pass metabolism

Lipophilic compounds – extensive Lipophilic compounds – extensive metabolism metabolism

Polar metabolites – excreted by urinePolar metabolites – excreted by urine


Biotransformation:

1st phase1st phaseOxidation Oxidation

(P450 (P450 system)system)

ReductionReductionHydrolysisHydrolysis

2nd phase-2nd phase-conjugationconjugation

Sulphuric acidSulphuric acidGlucuronic ac.Glucuronic ac.GlycineGlycineCysteineCysteineGlutathioneGlutathione


Oxidation of alcoholsOxidation of alcohols


Oxidation of unsaturated Oxidation of unsaturated bondsbonds


O-DealkylationO-Dealkylation


N-DealkylationN-Dealkylation


N-OxidationN-Oxidation


S-OxidationS-Oxidation


Oxidative desulphuration


Oxidative deaminationOxidative deamination


Reduction of Reduction of aldehydes, ketonesaldehydes, ketones


Reduction of Reduction of nitrogroupsnitrogroups


Hydrolysis of estersHydrolysis of esters


Hydrolysis of amidesHydrolysis of amides


Hydrolysis of Hydrolysis of benzodiazepinesbenzodiazepines


CONJUGATION CONJUGATION with GLYCINEwith GLYCINE

Biotransformation of Biotransformation of SalicylatesSalicylates


CONJUGATIOCONJUGATION of N of MORPHINEMORPHINE


cccc111111AAAAABiotransformation of heroin, Biotransformation of heroin, codeinecodeine


BiotransformationBiotransformation ofof cocainecocaine


Biotransformation of Biotransformation of methamphetaminemethamphetamine


Biotransformation of 9-THCBiotransformation of 9-THC


Nonspecific metabolites of some Nonspecific metabolites of some benzodiazepinesbenzodiazepines


Specific metabolites of Specific metabolites of flunitrazepamflunitrazepam


Metabolism of paracetamolMetabolism of paracetamolAcetaminophenAcetaminophen(COLDREX, KORYLAN, PANADOL)(COLDREX, KORYLAN, PANADOL)

Risk of hepatotoxicity Risk of hepatotoxicity Hepatoprotection Hepatoprotection Antidotum N-Acetylcystein Antidotum N-Acetylcystein


Why to care about Why to care about biotransformationbiotransformation

Development of a toxicological Development of a toxicological methodmethod

Interpretation of toxicological Interpretation of toxicological findingsfindings

Understanding of drug effectsUnderstanding of drug effectsCorrect and effective therapy, Correct and effective therapy,

reduction of adverse drug reduction of adverse drug effectseffects

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M. Balíková: The Fate of Poison1 TOXICOLOGY I. The fate of poison in organism M. Balíková